Ochronosis

Histopathology:

• Histologic features of both endogenous ochronosis (alkaptonuria) and exogenous ochronosis are similar.
• Curved banana shaped or rounded, yellow-brown to greyish-black coloured, ochronotic bodies/ochre pigmentation, affecting degenerating collagen and elastic fibre (green area), in the superficial dermis and connective tissue.
• Pigment incontinence with increased melanin in dermis and macrophages (blue area)
• Epidermis appears unremarkable.
• Features suggestive of exogenous ochronosis are solar elastosis-like changes in an interfollicular distribution, decreased basal keratinocyte pigmentation, pigmented colloid milia and sarcoid like granuloma.
• Sometimes ochronotic bodies are seen in pink amorphous material, referred as pigmented colloid milium.
• Methylene blue and Verhoeff van Gieson stain (elastic tissue stain) can be used to highlight the ochronotic bodies.

Difference	Alkaptonuria/ Endogenous ochronosis	Exogenous ochronosis/ Iatrogenic ochronosis
Incidence	Very rare	Relative common
Etiology	Inborn error of tyrosine metabolism, due to deficiency of homogentisate 1,2 dioxygenase/ homogentisic acid oxidase enzyme. Autosomal recessive disorder. Accumulation of homogentisic acid in connective tissue.	Localized inhibition of homogentisate 1,2 dioxygenase enzyme, due to excessive hydroquinone and phenol based topical cream. Other compound are resorcinol, mercury, picric acid and antimalarial drugs. Patient may have concurrent melasma. Accumulation of homogentisic acid in connective tissue.
Clinical features	In addition to skin hyperpigmentation, other sites like sclera, pinna, joint, kidney and heart valves that rich in elastic tissue are also affected. May present as eye, pinna, axillary and inguinal discoloration, backpain, heart murmur, urinary obstruction, arthropathy. Axillary Urine colour turns dark/black, if  expose to environment for long time.	Skin hyperpigmentation involving sun exposed areas like face, neck or upper limbs areas. Urine colour does not changes in exogenous ochronosis.
Diagnosis	Urine analysis for homogentisic acid (gas chromatography mass spectrometry). Evaluation for HGD mutations through PCR. Skin biopsy. Search for family history but it is not necessary for diagnosis	Detailed history for topical hydroquinone or phenol rich medication. Skin biopsy.
Management and prognosis	Dietary restriction of phenylalanine and tyrosine. Other specific organ affecting measures are cardiac valve replacement and joint replacement. Oral ascorbic acid and Nitisinone. Low protein diet. No cure but overall normal life expectancy with high morbidity.	Extensive hyperpigmentation may lead to cosmetic issue without effect on health. Discontinuation of hydroquinone and phenol based topical cream. Use of sunscreen, retinoic acid, topical steroid. Laser removal of skin pigmentation.